Functional Interaction between Adenosine A2A and mGlu5 Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGlu5R Binding in Mouse Hippocampus and Neuroblastoma Cell Line

(1) Background: Recently, we found that adenosine A(2A) receptor (A(2A)R) stimulation results in an increase in STEP phosphatase activity. In order to delve into the mechanism through which A(2A)R stimulation induced STEP activation, we investigated the involvement of mGlu5R since it is well documented that A(2A)R and mGlu(5)R physically and functionally interact in several brain areas. (2) Methods: In a neuroblastoma cell line (SH-SY5Y) and in mouse hippocampal slices, we evaluated the enzymatic activity of STEP by using a para-nitrophenyl phosphate colorimetric assay. A co-immunoprecipitation assay and a Western blot analysis were used to evaluate STEP/mGlu(5)R binding. (3) Results: We found that the A(2A)R-dependent activation of STEP was mediated by the mGlu5R. Indeed, the A(2A)R agonist CGS 21680 significantly increased STEP activity, and this effect was prevented not only by the A(2A)R antagonist ZM 241385, as expected, but also by the mGlu(5)R antagonist MPEP. In addition, we found that mGlu(5)R agonist DHPG-induced STEP activation was reversed not only by the mGlu(5)R antagonist MPEP but also by ZM 241385. Finally, via co-immunoprecipitation experiments, we found that mGlu(5)R and STEP physically interact when both receptors are activated (4) Conclusions: These results demonstrated a close functional interaction between mGlu(5) and A(2A) receptors in the modulation of STEP activity.